Study design
This was a single-center, randomized, prospective clinical trial and was performed in 6 ICUs in West China Hospital of Sichuan University. Randomisation was done by means of a computer-based random number table procedure, by staff not involved in treatment of the patients. Patients and therapists were not masked to the treatment. Patients data collection and analysis were masked to the treatment group allocation staff. The study was approved by the Ethics Committees of West China Hospital of Sichuan University (2017 − 102) and was registered at Chinese Clinical Trial Registry (www.chictr.org.cn, ChiCTR-IPR-17012629). Informed consents were obtained from patients or patients’ legal representatives.
Patients
Sixty-four critically ill patients (49 males and 15 females) with AKI or chronic kidney disease (CKD) receiving CRRT during September 2017 and September 2019 were successfully enrolled in this study. All the included participants who agreed with this study were randomly assigned to RCA-based CRRT with calcium-containing replacement solution (calcium-containing group, n = 35) or the calcium-free replacement solution (calcium-free group, n = 29).
Inclusion and exclusion criteria
The inclusion criteria were as follows: 1) Critically ill patients who need renal replacement therapy, such as AKI, ESRD or CKD, acute drug or pesticide intoxication patients, etc.; 2) Hemodynamically stable and suitability for CRRT with continuous venovenous hemodiafiltration (CVVHDF) modality; 3) Age between 18 to 80 years old; 4) Informed consent was given after enrolment. Patients were excluded for the study if they fulfilled these exclusion criteria: 1) Patients with citrate anticoagulant contraindications, such as sever liver failure, irreversible hypotension or hypoxemia; 2) Organ transplant patients; 3) Expected stay in ICU less than 24 hours; 4) Pregnant or breastfeeding; 5) Patients who cannot cooperate to the study because of mental diseases or other reasons.
Intervention
Prismaflex (Baxter (China) Investment Co., Ltd, Shanghai) CRRT machine, AN69 ST150 hemofilters (Baxter (China) Investment Co., Ltd, Shanghai) were applied for the extracorporeal circuit system. The AN69 ST150 set was replaced every 72 hours regularly. Patients in both groups were treated with CVVHDF. Vascular access was provided by the insertion of a double lumen catheter into either the femoral vein (Baxter International Inc, GDHK-1325, 13Fr, 250 mm) or internal jugular vein (Baxter International Inc, GDHK-1215, 12Fr, 150 mm). Post-dilution mode was used and the CRRT dose was 20–35 ml/kg/h (dialysis: replacement fluid = 1:1). The blood flow was set as 150 mL/min and adjusted according to ionized calcium (iCa) concentration during treatment. Blood gas were tested by using a point-of-care blood gas analyzer (Cobas b123, Roche Diagnostics, Basel, Switzerland) at the beginning (0.5 hours, pre-filter), 2 hours and every 6 hours (pre- and post-filter) after starting CVVHDF. 4% trisodium citrate solution (200 mL, Qingshan Likang Pharmaceutical Co. Ltd., Chengdu, China) was pumped into the arterial line of the extracorporeal circuit at an initial rate of 170 mL/h in both groups, and was titrated at increment or decrement of 10 mL/h to achieve a target post-filter iCa level of 0.25–0.35 mmol/L and pre-filter iCa level of 0.90–1.20 mmol/L.
The commercial calcium-containing replacement solution (Qingshan Likang, Pharmaceutical Co. Ltd., Chengdu, China), which contained solution A (Glucose 10.6 mmol/L, Cl− 118 mmol/L, Mg2+ 0.797 mmol/L, Ca2+ 1.60 mmol/L, and Na+ 113 mmol/L) and solution B (5% sodium bicarbonate), was adopted in calcium-containing group. Two liters of solution A combined with 125 mL of solution B had a pH of 7.40 and contained glucose 10.0 mmol/L, Cl− 110 mmol/L, Mg2+ 0.75 mmol/L, Ca2+ 1.50 mmol/L, Na+ 141 mmol/L, and HCO3− 35 mmol/L. During RCA based CVVHDF, relatively small dose (exp. solution A/B: 2 L/40 mL) of 5% sodium bicarbonate (solution B) was delivered alone by a pump pre-filter; this dose could be adjusted at any time to correct for metabolic acidosis or alkalosis. 10% potassium chloride was also infused by was delivered by another pump pre-filter and the infusion dose as well as net ultrafiltration were adjusted according to the blood gas analysis results and clinical condition of the patient. 10% calcium gluconate was infused on an as-needed basis to maintain the target ionized calcium level as an intermittent intravenous bolus. Calcium-free replacement solution (Qingshan Likang, Pharmaceutical Co. Ltd., Chengdu, China), which contained solution A (Glucose 10.6 mmol/L, Cl− 115 mmol/L, Mg2+ 0.797 mmol/L, Ca2+ 0.0 mmol/L, and Na+ 113 mmol/L) and solution B (5% sodium bicarbonate), was used in calcium-free group. In order to replace calcium losses in blood, intravenous 10% calcium gluconate was administered continuously by a pump via a T-branch pipe in post-filter at a speed of 18–25 mL/h. Other preset parameters were in accordance with calcium containing group. The standard scheme for application of these two replacement solutions in RCA-based post-dilution CVVHDF is shown in Fig. 1.
The decisions to start or stop CRRT were carried out by clinicians in both ICU and Nephrology department. CRRT was delivered according to manufacturer’s specifications, including routinely circuit changes after 72 hours of use without clotting. CRRT was prescribed by nephrologists and delivered by nursing staff. Patients and treatment information was collected at a later time.
Adverse reactions
One of the most feared complication of patients in both groups during RCA-based CRRT was citrate accumulation. Hypocalcemia, metabolic acidosis and increased serum lactate levels were noticeable signs. An increased total/ionized calcium (Ca/Ca2+) ratio (> 2.5) was recognized as indicative of significant accumulation [18]. When citrate accumulation was suspected, the net citrate load administered to the patient would be decreased. RCA would be replaced by alternative circuit anticoagulation if irreversible citrate accumulation happened. Other adverse potential complications such as bleeding, hypernatremia or hyponatremia, metabolic alkalosis, paresthesia, twitching movement and cardiac dysrhythmia were recorded in both groups.
Study endpoints
The primary outcome was circuit lifespan (measured in hours). Circuit lifespan started from extracorporeal circulation of blood and ended when the circuit was clotting. The clotted circuit was characterized by having exceeded transmembrane pressure (TMP) over than 250 mm Hg and/or visible clotting in air-trap chamber. CRRT circuits might be stopped without clotting because of the following reasons: 1) used for 72 h (without clotting); 2) catheter dysfunction and a new vascular access needed to be established (defined as unclear); 3) stopped for treatment reasons like operations and hospital transfer (defined as unclear); 4) patient relinquished CRRT (defined as unclear). Taken together, there were three possible outcomes for the circuits: clotted, without clotting or unclear. Clotted and “without clotting” circuits were defined as circuits with clear outcome.
The secondary endpoints included hospital mortality, length of ICU stays, kidney function recovery rate, complication incidence, as well as serum and effluent citrate and calcium concentration. Kidney function recovery was defined as normal serum creatinine (< 110 mmol/L) and urine output > 800 ml/day without diuretic applied according to previous studies [19, 20].
Sample Size
Sample size estimation was based on our previous circuit lifespan data of simplified RCA-based CRRT protocol. One hundred forty-eight sessions were performed and the mean hemofilter survival was 61.3 ± 21.6 h [14]. The study was designed to demonstrate a ≤ 20% difference in circuit lifespan with a 2-sided type I error of 0.05 and 80% power. According to the formula for calculating sample size of equivalent clinical trials [21], we set out to enroll 150 circuits (75 assigned to each group) to allow for a dropout rate of 15%. As the study was prematurely discontinued due to slow enrolment of patients, 149 circuits were included at the end of the study (Fig. 2).
Data collection
Demographic data was collected when CRRT initiated and treatment group allocation was masked to data collection staff. We gathered clinical information, the need for mechanical ventilation and vasopressors, sequential organ failure assessment (SOFA) score, and the following laboratory variables when starting CRRT: serum urea, creatinine, estimate glomerular filtration rate (eGFR), hemoglobin, platelet count, prothrombin time (PT), activated partial thromboplastin time (APTT), alanine aminotransferase (ALT), aspartate aminotransferase (AST) and total bilirubin levels. Other information during CRRT was recorded, such as blood flow rate, the amount of 4% trisodium citrate solution and 10% calcium gluconate administrated, filtration fraction, dialysate and replacement solution infusion rates, catheter sites, initial and withdraw TMP, circuit survival, causes of circuit replacement and adverse reactions. Other vital signs of the patients were also monitored regularly. The levels of serum and effluent total calcium (tCa) were measured by Roche Cobas c702 analyzer (Roche Diagnostics, Basel, Switzerland) in both groups and analyzed at the beginning (0.5 hours), 6 hours, 12 hours and then every 24 hours after CVVHDF. By the end of study, patients’ information about length of ICU stay, kidney function recovery and causes of death were collected.
Statistical analyses
SPSS (IBM SPSS Statistics 19.0, Chicago, IL, USA) was applied for all statistical analyses. Continuous numeric variables showed normal distributions were compared by t-test and presented as mean ± standard deviation (SD); Mann-Whitney U test and median (interquartile range, IQR) was used for non-normal distribution statistics. Categorical variables were analyzed by Pearson χ2 test or Fisher’s exact test and presented as the frequency and proportion. The Kaplan-Meier survival analysis using the log-rank test (Mantel-Cox test) was implemented for comparing the hemofilter survival within the two groups. Statistical significance was assigned to P values of < 0.05.